IllnessHypoparathyroidism, familial; differential diagnosis

NGS +

[Sanger]

Hypoparathyroidism is a disorder of calcium-phosphate metabolism that is characterized by hypocalcemia, hypercalciuria and hyperphosphatemia as a result of reduced parathyroid hormone (PTH) secretion. The following organ systems can be affected: skeleton, kidneys, skin, gastrointestinal tract, eyes and teeth. Neuromuscular and cardiovascular symptoms can also occur with possibly acute, life-threatening manifestations (e.g. tetany, seizures, cardiac arrhythmia) through to long-term complications (e.g. cerebral, vascular, renal or other ectopic calcifications).

Hypoparathyroidism is most frequently caused exogenously, e.g. following surgical excision or other damage to the parathyroid glands. However, hypoparathyroidism can also occur as a result of a variety of genetic causes. The genetic causes are extremely heterogeneous; both isolated forms and syndromic forms are known. Different inheritance patterns may be present (autosomal dominant, autosomal recessive, X-linked, mitochondrial).

Pathogenic variants in the PTH, SOX3, CASR, GNA11 and GCM2 genes, among others, have been described in hypoparathyroidism. Hypoparathyroidism can occur as part of hereditary syndromic diseases, e.g. in microdeletion syndrome 22q11.2 (TBX1 gene), Kenney-Caffey syndrome (TBCE gene) and others. Antibodies against CaSR (Ca sensitive receptor) occur in polyglandular autoimmune polyendocrinopathy type 1 as a result of pathogenic variants in the AIRE gene (APECED syndrome)

Diseases characterized by resistance of the target organs to PTH are summarized under the term pseudohypoparathyroidism (PHP). They are caused, among other things, by maternally inherited changes in the imprinted GNAS gene, which codes for the Gsα protein. Other genes from the GNAS pathway can also lead to PHP (e.g. PRKAR1A).

Pseudopseudohypoparathyroidism (PPHP) is characterized, among other things, by reduced Gsα activity without PTH resistance and is caused by paternally inherited loss-of-function variants in the GNAS gene.

Due to the pronounced heterogeneity of the above-mentioned clinical pictures, a genetic cause cannot be ruled out if no pathogenic variant is detected in the genetic analyses performed.

Hypoparathyroidism and pseudohypoparathyroidism - Endotext - NCBI Bookshelf (nih.gov)

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement - PMC (nih.gov)

https://register.awmf.org/assets/guidelines/174-005l_S1_Hypoparathyreoidismus-Pseudohypoparathyreoidismus_2022-07.pdf

https://www.ncbi.nlm.nih.gov/books/NBK441899/

Hypoparathyroidism and pseudohypoparathyroidism - Endotext - NCBI Bookshelf (nih.gov)

Hypoparathyroidism and pseudohypoparathyroidism - PubMed (nih.gov)

• Alias: Hyperparathyroidism, neonatal
• Allelic: ACTH-independent macronodular adrenal hyperplasia (GNAS)
• Allelic: Conotruncal anomaly face syndrome (TBX1)
• Allelic: DiGeorge syndrome (TBX1)
• Allelic: Encephalopathy, progressive, with amyotrophy + optic atrophy (TBCE)
• Allelic: Epilepsy idiopathic generalized, susceptibility to, 8 (CASR)
• Allelic: Hyperparathyroidism 4 (GCM2)
• Allelic: Hypocalcemia, AD (CASR)
• Allelic: Hypocalcemia, AD, with Bartter syndrome (CASR)
• Allelic: Hypocalciuric hypercalcemia, type I (CASR)
• Allelic: Hypocalciuric hypercalcemia, type II (GNA11)
• Allelic: Kenny-Caffey syndrome, type 1 (TBCE)
• Allelic: McCune-Albright syndrome, somatic, mosaic (GNAS)
• Allelic: Osseous heteroplasia, progressive (GNAS)
• Allelic: Pituitary adenoma 3, multiple types, somatic (GNAS)
• Allelic: Tetralogy of Fallot (TBX1)
• Allelic: Velocardiofacial syndrome (TBX1)
• Autoimmune polyendocrinopathy syndrome , type I, with/-out reversible metaphyseal dysplasia (AIRE)
• Hyperparathyroidism, neonatal (CASR)
• Hypocalcemia, AD 2 (GNA11)
• Hypoparathyroidism, familial isolated 1 (PTH)
• Hypoparathyroidism, familial isolated 2 (GCM2)
• Hypoparathyroidism, sensorineural deafness + renal dysplasia (GATA3)
• Hypoparathyroidism-retardation-dysmorphism syndrome (TBCE)
• Pseudohypoparathyroidism Ia, Ib, Ic (GNAS)
• Pseudohypoparathyroidism, type IB (STX16)
• Pseudopseudohypoparathyroidism (GNAS)